Differential expression and function of human IL-12Rβ2 polymorphic variants

• Published in: Molecular immunology 2013-12, Vol.56 (4), p.380-389
• Main Authors: de Paus, Roelof A., Geilenkirchen, Marije A., van Riet, Sander, van Dissel, Jaap T., van de Vosse, Esther
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Autoimmunity; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Cytokines - metabolism; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Profiling; Humans; IL-12; IL-12Rβ2; IL12RB2; Intercellular Adhesion Molecule-1 - metabolism; Interleukin-12 - pharmacology; Mutation; Phosphorylation - drug effects; Polymorphism; Polymorphism, Single Nucleotide; Protein Binding - genetics; Receptors, Interleukin-12 - genetics; Receptors, Interleukin-12 - metabolism; Receptors, Interleukin-12 - physiology; STAT4 Transcription Factor - metabolism
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2013.07.002

•Development of a model to study the effect of amino acid changes in IL-12Rβ2.•The model can distinguish between deleterious, intermediate and innocuous effects.•The IL-12Rβ2 variants N271Y, R313G, A604V and L808R affect receptor function. The receptor for interleukin-12, formed by IL-12Rβ1 and IL-12Rβ2, mediates the type I immune responses of various types of lymphocytes. Polymorphisms in IL12RB2, the gene encoding IL-12Rβ2, were reported to be associated with several immune related diseases, such as Crohn's disease. Because the IL23R and IL12RB2 genes are located in close proximity on the genome, the reported associations might also be attributable to linked polymorphisms in IL23R, which were found to be associated with immune related diseases as well. To clarify the role of IL-12Rβ2 in immune diseases, we investigated the functional consequences of thirteen amino acid substitutions in IL-12Rβ2. We developed a model with retroviral expression of IL-12Rβ2 in B cell lines. With the use of this model the expression and function of the variants was compared within the same genetic background. Four of the IL-12Rβ2 variants, N271Y, R313G, A604V and L808R showed reduced IL-12 responses compared to the wild type variant. Two of these are relatively common in some populations and may be used in future association studies to reveal a role for IL-12 in infectious and/or immune related diseases.